Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort

Abstract

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5′‐untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long‐read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92‐138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26‐380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID.

30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?

“…The number of pathological CGG repeats was estimated to range from 61 to 500 repeats whereas in control individuals this number varies from 6 to 60 and CGG repeats can be interrupted by AGG motifs. 54,55,116 CGG expansions associated with NIID are not consistently associated with DNA hypermethylation and they do not alter the expression of NOTCH2NLC, but anti-sense transcripts are specifically produced in affected individuals. 54,55 This suggests pathophysiological mechanisms possibly similar to FXTAS, with a probable gain of toxic function at the RNA level and the eventual existence of repeat-associated non-AUG (RAN) translation.…”

An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics

“…Of note, the expansion was detected or confirmed using long-read sequencing. Some patients have been identified to have ‘AGG’ interruptions, with evidence in a small East–Asian cohort showing interruptions may be linked to earlier age of onset [ 24 ]. NIID is a neurodegenerative condition characterized by eosinophilic intranuclear inclusions in neuronal and glial cells, which have characteristic findings on brain MRI, including high diffusion-weighted imaging signals along the corticomedullary junction [ 4 , 95 , 152 ].…”

NOTCH2NLC-related disorders: the widening spectrum and genotype–phenotype correlation

“…Recently, GGC repeat expansion in the 5′ UTR of NOTCH2NLC was identified as the most common causative factor of NIID 4–9. The GGC repeat expansion accounts for nearly 100% of NIID cases in China4 7 and Japan5 6 but almost nil in the European population 9.…”

“…In addition, the interruptions in GGC repeats were found to modify the age of onset,16 clinical manifestations17 and somatic stability 18. An expanded GGC repeats with GGA interruptions instead of a pure GGC repeat expansion may cause a muscle weakness-dominant phenotype and an earlier age at onset 6 8. However, whether and how interruptions modify the NIID clinical phenotype remains elusive.…”

“…Four paralogous genes ( NOTCH2NLA , NOTCH2NLB , NOTCH2NLC and NOTCH2NLR ) have been identified, all residing in chromosome 1 54. GGC repeat expansion in the 5′ UTR of NOTCH2NLC has been found to be associated with NIID,4–8 leukoencephalopathy,33 ET,20–23 MSA,27 PD,28 31 ALS53 and OPDM,40 41 most of which are neurodegenerative disorders, suggesting a contributing role of NOTCH2NLC GGC repeat expansion in neurodegeneration. Three possible disease-causing mechanisms may underly the pathogenesis of NOTCH2NLC GGC repeat expansion: loss-of-function, RNA toxicity, and RAN toxicity.…”